PROJECT SUMMARY Autism Spectrum Disorder (ASD) describes a collection of neurodevelopmental abnormalities of varying severity that have been estimated to impact more than 1% of Americans, mostly males. ASD can negatively impact one?s ability to communicate and navigate social interactions. In its most severe forms, ASD also can lead to self-destructive, repetitive behaviors that require afflicted persons be institutionalized for their own safety. The prevalence of ASD has grown in recent decades; one explanation for this trend is that poorly appreciated environmental factors have raised the underlying incidence of the disorder. Early in utero exposure to circulating maternal antibodies (Ab) has been implicated increasingly as a major risk factor for children to develop ASD. This model posits that maternal antibodies bind to proteins on the surface of the fetal brain and interfere with normal development. It is supported by studies in mice and monkeys that have revealed that sera purified from mothers with ASD children, when injected before a critical point in gestation, can trigger changes in brain anatomy and ASD-like behavioral phenotypes in offspring. Indeed, > 10% of ASD cases may be explained by fetal exposure to maternal brain-reactive antibodies. Yet this mode of pathogenesis has two salient consequences: 1) maternal Ab represent detectable biomarkers that can indicate ASD risk, and 2) ASD risk could be mitigated by treating mothers with a ?decoy antigen? to neutralize deleterious antibodies. Spark2Flame (S2F) seeks to develop clinical products in both of these areas. During Phase I work, S2F showed in mice that prenatal exposure to antibodies that bind the transmembrane protein Caspr2 disrupts brain development and causes behavioral phenotypes in male offspring. This effect, which recapitulates the sex-bias ASD shows in humans, was corroborated in several distinct mouse models. Thus, these results strongly recommend Caspr2-reactive antibodies as targets for a ?decoy antigen? therapy. In this Phase II SBIR, S2F will test a panel of therapeutic biologics based on the Caspr2 extracellular domain fused to IgG Fc domain to increase stability. In Aim 1, candidates will be characterized stability and for ability to neutralize Caspr2-reactive antibodies, and the panel will be narrowed to two lead candidates (leads). Aims 2 and 3 conduct preliminary toxicology studies in adult and fetal mice, respectively. In Aim 4, S2F explores the immunotoxicity of leads in mice with humanized immune systems. Aim 5 tests the efficacy of leads for blocking the pathogenic effects of polyclonal maternal Caspr2 immunity by assaying the brain morphology and behavioral phenotypes of offspring. Successful completion of this Phase II project will establish a strong foundation for continued pre-clinical development of leads, which ultimately may result in a first-in-class therapy to mitigate ASD risk caused by a class of pathologic maternal antibodies.